Medicament incorporation matrix

ABSTRACT

A coating composition, in both its uncrosslinked and crosslinked forms, for use in delivering a medicament from the surface of a medical device positioned in vivo. Once crosslinked, the coating composition provides a gel matrix adapted to contain the medicament in a form that permits the medicament to be released from the matrix in a prolonged, controlled, predictable and effective manner in vivo. A composition includes a polyether monomer, such as an alkoxy poly(alkylene glycol), a carboxylic acid-containing monomer, such as (meth)acrylic acid, a photoderivatized monomer, and a hydrophilic monomer such as acrylamide.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a continuation of provisional U.S. patentapplication filed 15 Aug. 2000 and assigned Ser. No. 60/225,465, theentire disclosure of which is incorporated herein by reference.

GOVERNMENT FUNDING

The United States government may have certain rights in this inventionby virtue of NIH Grant No. 1 R43 AR 44758-01.

TECHNICAL FIELD

In one aspect, the present invention relates to the delivery ofmedicaments, such as drugs, from within or upon the surface ofimplantable medical devices. In another aspect, the invention relates tohydrogel matrices containing these and other medicaments.

BACKGROUND OF THE INVENTION

Hydrogels are typically described as hydrophilic polymer networks thatare capable of absorbing large amounts of water, yet are themselvesinsoluble because of the presence of physical or chemical crosslinks,entanglements or crystalline regions. Hydrogels have found extensive usein biomedical applications, including as coatings and drug deliverysystems. Hydrogels are often sensitive to the conditions of theirsurrounding environment, such that the swelling ratio of the materialscan be affected by temperature, pH, ionic strength and/or the presenceof a swelling agent. Several parameters can be used to define orcharacterize hydrogels, including the swelling ratio under changingconditions, the permeability coefficient of certain solutes, and themechanical behavior of the hydrogel under conditions of its intendeduse. When used as drug delivery systems these changes in the environmentcan often be controlled or predicted in order to regulate drug release.(See Bell and Peppas, cited below).

A particular type of hydrogel that has been described in recent yearsinvolves the combination of poly(methacrylic acid) (“PMAA”) backbonesand polyethylene glycol (“PEG”) grafts. For instance, Mathur, et al., J.Controlled Release 54(2):177–184 (1998) describe “responsive” hydrogelnetworks of this type. The hydrogels exhibit swelling transitions, invarious solvent systems, and in response to external stimuli. Thesetransitions, in turn, can lead to the formation or disruption ofhydrogen-bonded complexes between the backbone and graft portions. Thearticle describes the role of hydrophobic interactions in stabilizingthe complexes.

A variety of references further describe the preparation and use ofhydrogels for the delivery of medicaments, including those hydrogelsbased on the combination of polyalkylene glycols andpoly(meth)acrylates. See, for instance, U.S. Pat. Nos. 5,884,039 and5,739,210, which describe polymers having reversible hydrophobicfunctionalities, e.g., polymers having Lewis acid and Lewis basesegments. The segments are hydrophilic and will either swell or dissolvein water. When incorporated into a polymer, the segments formwater-insoluble or hydrophobic complexes. Upon changes in pH,temperature or solvent type, the complexes can dissociate, giving largetransitions in viscosity, emulsification ability and mechanicalstrength. The polymers are said to be useful as reversible emulsifiers,super-absorbing resins, or as coatings for pharmaceutical agents.

See also, Scott, et al., Biomaterials 20(15):1371–1380 (1999), whichdescribes the preparation of ionizable polymer networks prepared fromoligo(ethylene glycol) multiacrylates and acrylic acid using bulkphotopolymerization techniques. The networks are described for use inthe preparation of controlled release devices for solutes.

Finally, C. L. Bell, and N. A. Peppas, J. Biomater. Sci. Polymer Edn.7(8):671–683 (1996) and C. L. Bell and N. A. Peppas, Biomaterials17:1203–1218 (1996) each describe the synthesis and properties ofgrafted P(MAA-g-EG) copolymers. The copolymers permit the reversibleformation of complexes under appropriate conditions due to hydrogenbonding between the carboxylic acid groups of the PMAA and the oxygenatoms of the PEG chains, resulting in pH-sensitive swelling behavior.Complexation occurs at low pH, resulting in increased hydrophobicity inthe polymer network. At higher pH values, the acid groups become ionizedand the hydrogen bonding breaks down. The papers studied this pHsensitive swelling behavior in relation to the use of such materials incontrolled release drug delivery and bioseparations.

The Bell and Peppas papers exemplified the swelling behavior ofP(MAA-g-EG) samples containing 40:60, 50:50 and 60:40 ratios (weightpercent) of PMAA:PEG, using PEG grafts having molecular weights of 200,400 and 1000. The resultant hydrogels were evaluated by several means,including mechanical testing to determine shear modulus. The authorsfound that as the molecular weight of the PEG graft was increased, themodulus of the networks decreased in both the complexed and uncomplexedstate.

When used for drug delivery, the materials prepared by Bell and Peppaswere typically used as free standing hydrogel membranes, with no mentionof their use upon a surface, let alone the surface of an implantedmedical device. Nor, in turn, do these references provide any suggestionof the manner in which such matricies might be applied to any suchsurface.

Those references that do describe the delivery of medicaments fromimplanted devices tend to rely on approaches quite different fromimplanted hydrogels. The continuing development and use of implantablemedical devices has led to the corresponding development of a variety ofways to deliver antibiotics and/or antiseptics to the implant site, inorder to prevent potential infections associated with such devices.

For instance, a significant percent of fracture fixation devices (pins,nails, screws, etc.) and orthopedic joint implants become infected. Cureof infected orthopedic implants, such as joint prostheses, usuallyrequires both removal of the prosthesis and administration of a longcourse of antibiotics. In most cases, this is followed byre-implantation of a new joint prosthesis weeks or months later, aftermaking sure that the infection has been eradicated.

As described in the patents to Darouiche, cited below, considerableamount of attention and study has therefore been directed towardpreventing colonization of bacterial and fungal organisms on thesurfaces of orthopedic implants by the use of antimicrobial agents, suchas antibiotics, bound to the surface of the materials employed in suchdevices. The objective of such attempts has been to produce a sufficientbacteriostatic or bactericidal action to prevent colonization.

Various methods have previously been employed to coat the surfaces ofmedical devices with an antibiotic. For example, one method involvesapplying or absorbing to the surface of the medical device a layer ofsurfactant, such as tridodecylmethyl ammonium chloride (“TDMAC”)followed by an antibiotic coating layer.

A further method known to coat the surface of medical devices withantibiotics involves first coating the selected surfaces withbenzalkonium chloride followed by ionic bonding of the antibioticcomposition. See, e.g., Solomon, D. D. and Sherertz, R. J., J.Controlled Release, 6:343–352 (1987) and U.S. Pat. No. 4,442,133. Yetother methods of coating surfaces of medical devices with antibioticsare taught in U.S. Pat. No. 4,895,566 (a medical device substratecarrying a negatively charged group having a pK of less than 6 and acationic antibiotic bound to the negatively charged group); U.S. Pat.No. 4,917,686 (antibiotics are dissolved in a swelling agent which isabsorbed into the matrix of the surface material of the medical device);U.S. Pat. No. 4,107,121 (constructing the medical device with ionogenichydrogels, which thereafter absorb or ionically bind antibiotics); U.S.Pat. No. 5,013,306 (laminating an antibiotic to a polymeric surfacelayer of a medical device); and U.S. Pat. No. 4,952,419 (applying a filmof silicone oil to the surface of an implant and then contacting thesilicone film bearing surface with antibiotic powders).

See also Ding et al., (U.S. Pat. No. 6,042,875), which describes acoating that permits timed or prolonged pharmacological activity on thesurface of medical devices through a reservoir concept. Specifically,the coating comprises at least two layers: an outer layer containing atleast one drug-ionic surfactant complex overlying a reservoir layer ortie layer containing a polymer and the drug which is substantially freeof an ionic surfactant. Upon exposure to body tissue of a medical devicecovered with such coating, the ionically complexed drug in the outerlayer is released into body fluid or tissue. Following release of suchcomplexed drug, the ionic surfactant complex sites in the outer layerare left vacant.

After insertion of a medical device such as an orthopedic implant, theantibiotics and/or antiseptics quickly leach from the surface of thedevice into the surrounding environment. Over a relatively short periodof time, the amount of antibiotics and/or antiseptics present on thesurface decreases to a point where the protection against bacterial andfungal organisms is no longer effective. Furthermore, duringimplantation of orthopedic fracture fixation devices, such asintramedullary nails and external fixation pins, much of theantimicrobial coating sloughs off due to grating of the coated implantagainst the bone during insertion of the implant.

Hence, for some implants, and particularly those that both remain in thebody for extended periods of time and that undergo tortuous processingin the course of their implantation or use, medicament coatings continueto be sought to provide improved durability.

U.S. Pat. No. 5,853,745 (Darouiche), describes a durable antimicrobialcoated orthopedic device or other medical implant having a durablematerial layer that decreases the rate of leaching of antimicrobialagents into the surrounding environment. The patent provides anantimicrobial coated medical implant or orthopedic device havingmechanical resiliency to minimize or avoid sloughing of theantimicrobial layer from the device during insertion. The medicalimplant has one or more of its surfaces coated with a compositioncomprising an antimicrobial coating layer comprising an antimicrobialagent in an effective concentration to inhibit the growth of bacterialand fungal organisms, and a protective coating layer formed over saidantimicrobial coating layer.

When used as drug release coatings on devices, however, the varioussystems described above suffer from several drawbacks, e.g., in terms ofthe thickness of the coatings necessary to provide suitable amounts ofdrug, the kinetics (e.g., overall period of release), and the durabilityor tenacity of the coating itself. In spite of the various attempts andprogress made to date, it remains clear that the need for a coatingcomposition that provides an optimal combination of such properties ascoating thickness, drug release profile, durability, swellability,generic applicability, and surface independence remains unmet.

Improved coatings for use on implanted devices, in order to providemedicament release in situ, are clearly needed.

SUMMARY OF THE INVENTION

The present invention provides a crosslinkable coating composition, inboth its uncrosslinked and crosslinked forms, for use in delivering amedicament from the surface of a medical device positioned in vivo. Oncecrosslinked, the coating composition provides a gel matrix adapted tocontain the medicament in a form that permits the medicament to bereleased from the matrix in a prolonged, controlled, predictable andeffective manner in vivo. The combination of gel matrix and medicamentcan be provided in any suitable manner and at any suitable time, e.g.,the medicament can be included in one or more components of theuncrosslinked composition and/or it can be incorporated into the formedor forming matrix, e.g., at the time of use, and before, during, orafter crosslinking the composition or implanting the thus-coated deviceinto a tissue site. When applied as a coating to the surface of amedical device, a gel matrix can be formed thereon by a process thatincludes a complexation reaction between carboxylic acid groups andether groups. The complexation reaction serves to both improve thedurability and tenacity of the coating and prolong the delivery of themedicaments incorporated into the matrix.

In a preferred embodiment, the coating composition preferably comprisesa polymeric reagent formed by the polymerization of the followingmonomers:

a) about 1 to about 20 mole % of a polyether monomer,

b) about 5 to about 75 mole % of a carboxylic acid-containing monomer,such that the effective ratio of ether groups to carboxylic acid groupsin the resultant copolymer is between about 1 to 1 and about 10 to 1,

c) optionally, about 0.1 to about 10 mole % of a photoderivatizedmonomer, and

d) an amount of a hydrophilic monomer suitable to bring the compositionto 100% (e.g., about 0 to about 93.9 mole % of a hydrophilic monomer).

When the polymeric reagent is applied as a coating to the surface of amedical device, noncovalent interactions occur between carboxylic acidgroups and ether groups, thus contributing to the formation of a gelmatrix. The application of UV light provides photochemical attachment tothe substrate as well as the formation of covalent crosslinks within thematrix. The matrix, thus formed, provides both improved durability andtenacity of the coating in a manner that prolongs the delivery of themedicaments incorporated into the matrix.

In a particularly preferred embodiment, for instance, the uncrosslinkedcomposition comprises a polymeric reagent formed by the polymerizationof the following monomers:

a) methoxy poly(ethylene glycolmethacrylate) (“methoxyPEGMA”), as thepolyether monomer, in an amount of between about 5 and about 15 mole %,

b) (meth)acrylic acid, as the carboxylic acid-containing monomercomponent, present in an amount of between about 30 and about 50 mole %,

c) photoderivatized monomer, present in an amount of between about 1 toabout 7 mole %, and

d) acrylamide monomer, as a hydrophilic monomer, present in an amount ofbetween about 30 and about 70 mole %.

Without intending to be bound by theory, it is believed that uponapplication of a solution of the uncrosslinked composition to thesurface of a medical device, and UV illumination to activate thephotogroups, that a covalently bound matrix is thus formed on thesurface of the device. This matrix contains both carboxylic acid groupsand ether groups which, under the appropriate conditions, formcomplexes. These complexes, in turn, increase the hydrophobicity of thematrix and appear to improve the durability and tenacity of the matrix,and prolong the release of the medicaments incorporated into the matrix.

A matrix of this invention provides an optimal and improved combinationof such properties as medicament release profile, durability, tenacity,solubility, swellability, and coating thickness. Such a matrix can beused with a wide range of surface materials and configurations, and inturn, is widely applicable and useful with a variety of implanteddevices.

DETAILED DESCRIPTION

The composition of this invention preferably includes between about 1and about 20 mole % of a polyether monomer and preferably from about 5to about 15 mole %. Most preferably, the polyether monomer is used at afinal concentration of about 8 to about 12 mole %. The term “mole %” asused herein will be determined by the molecular weight of the monomercomponents.

The polyether monomer is preferably of the group of molecules referredto as alkoxy (poly)alkyleneglycol (meth)acrylates. The alkoxysubstituents of this group may be selected from the group consisting ofmethoxy, ethoxy, propoxy, and butoxy. The (poly)alkylene glycolcomponent of the molecule may be selected from the group consisting of(poly)propylene glycol and (poly)ethylene glycol. The (poly)alkyleneglycol component preferably has a nominal weight average molecularweight ranging from about 200 g/mole to about 2000 g/mole, and ideallyfrom about 800 g/mole to about 1200 g/mole. Examples of preferredpolyether monomers include methoxy PEG methacrylates, PEG methacrylates,and (poly)propylene glycol methacrylates. Such polyether monomers arecommercially available, for instance, from Polysciences, Inc.,(Warrington, Pa.).

A composition of this invention preferably includes between about 5 toabout 75 mole % of a carboxylic acid-containing monomer, such that theeffective ratio of ether groups to carboxylic acid groups in theresultant copolymer is between about 1 to 1 and about 10 to 1. Preferredconcentrations of the carboxylic acid-containing monomer are betweenabout 30 to about 50 mole %. Most preferably, the carboxylicacid-containing monomer is used at a concentration between about 30 toabout 40 mole %. These monomers can be obtained commercially, forinstance, from Sigma-Aldrich, Inc. (St. Louis, Mo.).

Preferred carboxylic acid-containing monomers are selected from carboxylsubstituted ethylene compounds, also known as alkenoic acids. Examplesof particularly preferred carboxylic acid-containing monomers includeacrylic, methacrylic, maleic, crotonic, itaconic, and citraconic acid.Most preferred examples of carboxylic acid-containing monomers includeacrylic acid and methacrylic acid.

A composition of the present invention preferably includes between about0.1 and about 10 mole % of a photoderivatized monomer, more preferablybetween about 1 and about 7 mole %, and most preferably between about 3and about 5 mole %.

Examples of suitable photoderivatized monomers are ethylenicallysubstituted photoactivatable moieties which includeN-[3-(4-benzoylbenzoamido)propyl]methacrylamide (“BBA-APMA”),4(2-acryloxyethoxy)-2-hydroxybenzophenone,4-methacryloxy-2-hydroxybenzophenone,4-methacryloxy-2-hydroxybenzophenone, 9-vinyl anthracene, and9-anthracenylmethyl methacrylate. An example of a preferredphotoderivatized monomer is BBA-APMA.

Photoreactive species are defined herein, and preferred species aresufficiently stable to be stored under conditions in which they retainsuch properties. See, e.g., U.S. Pat. No. 5,002,582, the disclosure ofwhich is incorporated herein by reference. Latent reactive groups can bechosen that are responsive to various portions of the electromagneticspectrum, with those responsive to ultraviolet and visible portions ofthe spectrum (referred to herein as “photoreactive”) being particularlypreferred.

Photoreactive species respond to specific applied external stimuli toundergo active specie generation with resultant covalent bonding to anadjacent chemical structure, e.g., as provided by the same or adifferent molecule. Photoreactive species are those groups of atoms in amolecule whose covalent bonds remain unchanged under conditions ofstorage but upon activation by an external energy source, form covalentbonds with other molecules.

The photoreactive species generate active species such as free radicalsand particularly nitrenes, carbenes, and excited states of ketones uponabsorption of electromagnetic energy. Photoreactive species can bechosen to be responsive to various portions of the electromagneticspectrum, and photoreactive species that are responsive to, e.g.,ultraviolet and visible portions of the spectrum, are preferred and canbe referred to herein occasionally as “photochemical group” or“photogroup.”

The photoreactive species in photoreactive aryl ketones are preferred,such as acetophenone, benzophenone, anthraquinone, anthrone, andanthrone-like heterocycles, i.e., heterocyclic analogs of anthrone suchas those having N, O, or S in the 10-position, or their substituted,e.g., ring substituted, derivatives. Examples of preferred aryl ketonesinclude heterocyclic derivatives of anthrone, including acridone,xanthone, and thioxanthone, and their ring substituted derivatives.Particularly preferred are thioxanthone, and its derivatives, havingexcitation energies greater than about 360 nm.

The functional groups of such ketones are preferred since they arereadily capable of undergoing the activation/inactivation/reactivationcycle described herein. Benzophenone is a particularly preferredphotoreactive moiety, since it is capable of photochemical excitationwith the initial formation of an excited singlet state that undergoesintersystem crossing to the triplet state. The excited triplet state caninsert into carbon-hydrogen bonds by abstraction of a hydrogen atom(from a support surface, for example), thus creating a radical pair.Subsequent collapse of the radical pair leads to formation of a newcarbon-carbon bond. If a reactive bond (e.g., carbon-hydrogen) is notavailable for bonding, the ultraviolet light-induced excitation of thebenzophenone group is reversible and the molecule returns to groundstate energy level upon removal of the energy source. Photoactivatiblearyl ketones such as benzophenone and acetophenone are of particularimportance inasmuch as these groups are subject to multiple reactivationin water and hence provide increased coating efficiency.

The azides constitute a preferred class of photoreactive species andinclude derivatives based on arylazides (C₆R₅N₃) such as phenyl azideand particularly 4-fluoro-3-nitrophenyl azide, acyl azides (—CO—N₃) suchas benzoyl azide and p-methylbenzoyl azide, azido formates (—O—CO—N₃)such as ethyl azidoformate, phenyl azidoformate, sulfonyl azides(—SO₂—N₃) such as benzenesulfonyl azide, and phosphoryl azides (RO)₂PON₃such as diphenyl phosphoryl azide and diethyl phosphoryl azide. Diazocompounds constitute another class of photoreactive species and includederivatives of diazoalkanes (—CHN₂) such as diazomethane anddiphenyldiazomethane, diazoketones (—CO—CHN₂) such as diazoacetophenoneand 1-trifluoromethyl-1-diazo-2-pentanone, diazoacetates (—O—CO—CHN₂)such as t-butyl diazoacetate and phenyl diazoacetate, andbeta-keto-alpha-diazoacetates (—CO—CN₂—CO—O—) such as t-butyl alphadiazoacetoacetate. Other photoreactive species include the diazirines(—CHN₂) such as 3-trifluoromethyl-3-phenyldiazirine, and ketenes(—CH═C═O) such as ketene and diphenylketene.

Upon activation of the photoreactive species, the coating agents arecovalently bound to each other and/or to the material surface bycovalent bonds through residues of the photoreactive species. Exemplaryphotoreactive species, and their residues upon activation, are shown asfollows.

Residue Photoreactive Group Functionality aryl azides amine R—NH—R′ acylazides amide R—CO—NH—R′ azidoformates carbamate R—O—CO—NH—R′ sulfonylazides sulfonamide R—SO₂—NH—R′ phosphoryl azides phosphoramide(RO)₂PO—NH—R′ diazoalkanes new C—C bond diazoketones new C—C bond andketone diazoacetates new C—C bond and ester beta-keto-alpha-diazo- newC—C bond and acetates beta-ketoester aliphatic azo new C—C bonddiazirines new C—C bond ketenes new C—C bond photoactivated ketones newC—C bond and alcohol

The coating agents of the present invention can be applied to anysurface having carbon-hydrogen bonds, with which the photoreactivespecies can react to immobilize the coating agents to surfaces. Examplesof suitable surfaces are described in more detail below.

A composition of the present invention includes about 0 to about 93.9mole %, preferably from about 30 to about 70 mole %, and most preferablyfrom about 40 to about 60 mole % of a suitable hydrophilic monomercomponent. Suitable hydrophilic monomers provide an optimal combinationof such properties as water solubility, biocompatability, andwettability. Most preferably, the hydrophilic monomer improves orprovides the resultant polymeric complex with improved water solubility,though noting that the carboxylic acid-containing monomer may behydrophilic as well, and can contribute to this effect.

Hydrophilic monomers are preferably taken from the group consisting ofalkenyl substituted amides. Examples of preferred hydrophilic monomersinclude acrylamide, N-vinylpyrrolidone, methacrylamide, acrylamidopropanesulfonic acid (AMPS). Acrylamide is an example of a particularlypreferred hydrophilic monomer.

Such monomers are available commercially from a variety of sources,e.g., Sigma-Aldrich, Inc. (St. Louis, Mo.) and Polysciences, Inc.(Warrington, Pa.).

The word “medicament”, as used herein, will refer to a wide range ofbiologically active materials or drugs that can be incorporated into acoating composition of the present invention. The substances to beincorporated preferably do not chemically interact with the compositionduring fabrication, or during the release process.

Additives such as inorganic salts, BSA (bovine serum albumin), and inertorganic compounds can be used to alter the profile of substance release,as known to those skilled in the art. The term “medicament”, in turn,will refer to a peptide, protein, carbohydrate, nucleic acid, lipid,polysaccharide or combinations thereof, or synthetic inorganic ororganic molecule, that causes a biological effect when administered invivo to an animal, including but not limited to birds and mammals,including humans. Nonlimiting examples are antigens, enzymes, hormones,receptors, peptides, and gene therapy agents. Examples of suitable genetherapy agents include a) therapeutic nucleic acids, including antisenseDNA and antisense RNA, and b) nucleic acids encoding therapeutic geneproducts, including plasmid DNA and viral fragments, along withassociated promoters and excipients. Examples of other molecules thatcan be incorporated include nucleosides, nucleotides, antisense,vitamins, minerals, and steroids.

Coating compositions prepared according to this process can be used todeliver drugs such as nonsteroidal anti-inflammatory compounds,anesthetics, chemotherapeutic agents, immunotoxins, immunosuppressiveagents, steroids, antibiotics, antivirals, antifungals, and steroidalantiinflammatories, anticoagulants. For example, hydrophobic drugs suchas lidocaine or tetracaine can be included in the coating and arereleased over several hours.

Classes of medicaments which can be incorporated into coatings of thisinvention include, but are not limited to, anti-AIDS substances,anti-cancer substances, antibiotics, anti-viral substances, enzymeinhibitors, neurotoxins, opioids, hypnotics, antihistamines,immunosuppresents (e.g., cyclosporin), tranquilizers, anti-convulsants,muscle relaxants and anti-Parkinson substances, anti-spasmodics andmuscle contractants, miotics and anti-cholinergics, iminunosuppressants(e.g. cyclosporine) anti-glaucoma solutes, anti-parasite and/oranti-protozoal solutes, anti-hypertensives, analgesics, anti-pyreticsand anti-inflammatory agents (such as NSAID's), local anesthetics,ophthalmics, prostaglandins, anti-depressants, anti-psychoticsubstances, anti-emetics, imaging agents, specific targeting agents,neurotransmitters, proteins and cell response modifiers. A more completelisting of classes of medicaments may be found in the PharmazeutischeWirkstoffe, ed. A. Von Kleemann and J. Engel, Georg Thieme Verlag,Stuttgart/New York, 1987, incorporated herein by reference.

Antibiotics are art recognized and are substances which inhibit thegrowth of or kill microorganisms. Antibiotics can be producedsynthetically or by microorganisms. Examples of antibiotics includepenicillin, tetracycline, chloramphenicol, minocycline, doxycycline,vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromycinand cephalosporins. Examples of cephalosporins include cephalothin,cephapirin, cefazolin, cephalexin, cephradine, cefadroxil, cefamandole,cefoxitin, cefaclor, cefuroxime, cefonicid, ceforanide, cefotaxime,moxalactam, ceftizoxime, ceftriaxone, and cefoperazone.

Antiseptics are recognized as substances that prevent or arrest thegrowth or action of microorganisms, generally in a nonspecific fashion,e.g., either by inhibiting their activity or destroying them. Examplesof antiseptics include silver sulfadiazine, chlorhexidine,glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenoliccompounds, iodophor compounds, quaternary ammonium compounds, andchlorine compounds.

Anti-viral agents are substances capable of destroying or suppressingthe replication of viruses. Examples of anti-viral agents includeα-methyl-P-adamantane methylamine), hydroxy-ethoxymethylguanine,adamantanamine, 5-iodo-2′-deoxyuridine, trifluorothymidine, interferon,and adenine arabinoside.

Enzyme inhibitors are substances which inhibit an enzymatic reaction.Examples of enzyme inhibitors include edrophonium chloride,N-methylphysostigmine, neostigmine bromide, physostigmine sulfate,tacrine HCL, tacrine, 1-hydroxy maleate, iodotubercidin,p-bromotetramisole, 10-(a-diethylaminopropionyl)-phenothiazinehydrochloride, calmidazolium chloride,hemicholinium-3,3,5-dinitrocatechol, diacylglycerol kinase inhibitor I,diacylglycerol kinase inhibitor II, 3-phenylpropargylaminie,N-monomethyl-L-arginine acetate, carbidopa, 3-hydroxybenzylhydrazineHCl, hydralazine HCl, clorgyline HCl, deprenyl HCl, L(−), deprenyl HCl,D(+), hydroxylamine HCl, iproniazid phosphate,6-MeO-tetrahydro-9H-pyrido-indole, nialamide, pargyline HCl, quinacrineHCl, semicarbazide HCl, tranylcypromine HCl,N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride,3-isobutyl-1-methylxanthne, papaverine HCl, indomethacind,2-cyclooctyl-2-hydroxyethylamine hydrochloride,2,3-dichloro-a-methylbenzylamine (DCMB),8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride,p-aminoglutethimide, p-aminoglutethimide tartrate, R(+),p-aminoglutethimide tartrate, S(−), 3-iodotyrosine,alpha-methyltyrosine, L(−), alpha -methyltyrosine, D L(−), cetazolamide,dichlorphenamide, 6-hydroxy-2-benzothiazolesulfonamide, and allopurinol.

Anti-pyretics are substances capable of relieving or reducing fever.Anti-inflammatory agents are substances capable of counteracting orsuppressing inflammation. Examples of such agents include aspirin(salicylic acid), indomethacin, sodium indomethacin trihydrate,salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal,diclofenac, indoprofen and sodium salicylamide. Local anesthetics aresubstances which have an anesthetic effect in a localized region.Examples of such anesthetics include procaine, lidocaine, tetracaine anddibucaine.

Imaging agents are agents capable of imaging a desired site, e.g.,tumor, in vivo. Examples of imaging agents include substances having alabel which is detectable in vivo, e.g., antibodies attached tofluorescent labels. The term antibody includes whole antibodies orfragments thereof.

Cell response modifiers are chemotactic factors such as platelet-derivedgrowth factor (pDGF). Other chemotactic factors includeneutrophil-activating protein, monocyte chemoattractant protein,macrophage-inflammatory protein, SIS (small inducible secreted),platelet factor, platelet basic protein, melanoma growth stimulatingactivity, epidermal growth factor, transforming growth factor (alpha),fibroblast growth factor, platelet-derived endothelial cell growthfactor, insulin-like growth factor, nerve growth factor and bonegrowth/cartilage-inducing factor (alpha and beta). Other cell responsemodifiers are the interleukins, interleukin inhibitors or interleukinreceptors, including interleukin 1 through interleukin 10; interferons,including alpha, beta and gamma; hematopoietic factors, includingerythropoietin, granulocyte colony stimulating factor, macrophage colonystimulating factor and granulocyte-macrophage colony stimulating factor;tumor necrosis factors, including alpha and beta; transforming growthfactors (beta), including beta-1, beta-2, beta-3, inhibin, activin, andDNA that encodes for the production of any of these proteins.

The coating composition of the present invention can be used incombination with a variety of devices, including those used on atemporary, transient or permanent basis upon and/or within the body.

Examples of medical devices suitable for the present invention include,but are not limited to catheters, implantable vascular access ports,blood storage bags, vascular stents, blood tubing, central venouscatheters, arterial catheters, vascular grafts, intraaortic balloonpumps, heart valves, cardiovascular sutures, total artificial hearts andventricular assist pumps, extracorporeal devices such as bloodoxygenators, blood filters, hemodialysis units, hemoperfusion units,plasmapheresis units, hybrid artificial organs such as pancreas or liverand artificial lungs, as well as filters adapted for deployment in ablood vessel in order to trap emboli (also known as “distal protectiondevices”).

Devices which are particularly suitable include vascular stents such asself-expanding stents and balloon expandable stents. Examples ofself-expanding stents useful in the present invention are illustrated inU.S. Pat. Nos. 4,655,771 and 4,954,126 issued to Wallsten and U.S. Pat.No.5,061,275 issued to Wallsten et al. Examples of appropriateballoon-expandable stents are shown in U.S. Pat. No. 4,733,665 issued toPalmaz, U.S. Pat. No. 4,800,882 issued to Gianturco and U.S. Pat. No.4,886,062 issued to Wiktor. Similarly, urinary implants such as drainagecatheters are also particularly appropriate for the invention.

The surfaces of the medical devices may be formed from polymeric,metallic and/or ceramic materials. Suitable polymeric materials include,without limitation, polyurethane and its copolymers, silicone and itscopolymers, ethylene vinyl-acetate, thermoplastic elastomers, polyvinylchloride, polyolefins, cellulosics, polyamides, polyesters,polysulfones, polytetrafluorethylenes, polycarbonates, acrylonitrilebutadiene styrene copolymers, acrylics, polylactic acid, polyglycolicacid, polycaprolactone, polylactic acid-polyethylene oxide copolymers,cellulose, collagens, and chitins.

Metallic materials include metals and alloys based on titanium (such asnitinol, nickel titanium alloys, thermo-memory alloy materials),stainless steel, tantalum, nickel-chrome, or cobalt-chromium (such thoseavailable under the tradenames Elgiloy™ and Phynox™). Metallic materialsalso include clad composite filaments, such as those disclosed in WO94/16646. Examples of ceramic materials include ceramics of alumina andglass-ceramics such as those available under the tradename Macor™.

The substrates that can be coated with a composition of the presentinvention include materials that are substantially insoluble in bodyfluids and that are generally designed and constructed to be placed inor onto the body or to contact fluid of the body. The substratespreferably have the physical properties such as strength, elasticity,permeability and flexibility required to function for the intendedpurpose; can be purified, fabricated and sterilized easily; willsubstantially maintain their physical properties and function during thetime that they remain implanted in or in contact with the body. Examplesof such substrates include: metals such as titanium/titanium alloys,TiNi (shape memory/super elastic), aluminum oxide, platinum/platinumalloys, stainless steels, MP35N, elgiloy, haynes 25, stellite, pyrolyticcarbon, silver or glassy carbon; polymers such as polyurethanes,polycarbonates, silicone elastomers, polyolefins including polyethylenesor polypropylenes, polyvinyl chlorides, polyethers, polyesters, nylons,polyvinyl pyrrolidones, polyacrylates and polymethacrylates such aspolymethylmethacrylate (“PMMA”), n-Butyl cyanoacrylate, polyvinylalcohols, polyisoprenes, rubber, cellulosics, polyvinylidene fluoride(“PVDF”), polytetrafluoroethylene, ethylene tetrafluoroethylenecopolymer (“ETFE”), acrylonitrile butadiene ethylene, polyamide,polyimide, styrene acrylonitrile, and the like; minerals or ceramicssuch as hydroxyapatite; human or animal protein or tissue such as bone,skin, teeth, collagen, laminin, elastin or fibrin; organic materialssuch as wood, cellulose, or compressed carbon; and other materials suchas glass, or the like.

Substrates made using these materials can be coated or remain uncoated,and derivatized or remain underivatized. Medical devices upon or intowhich the composition can be coated include, but are not limited to,surgical implants, prostheses, and any artificial part or device whichreplaces or augments a part of a living body or comes into contact withbodily fluids, particularly blood. The substrates can be in any shape orform including tubular, sheet, rod and articles of proper shape. Variousmedical devices and equipment usable in accordance with the inventionare known in the art. Examples of devices include catheters, suturematerial, tubing, and fiber membranes. Examples of catheters includecentral venous catheters, thoracic drain catheters, angioplasty ballooncatheters. Examples of tubing include tubing used in extracorporealcircuitry, such as whole blood oxygenators. Examples of membranesinclude polycarbonate membranes, haemodialysis membranes, membranes usedin diagnostic or biosensor devices. Also included are devices used indiagnosis, as well as polyester yarn suture material such aspolyethylene ribbon, and polypropylene hollow fiber membranes.

Further illustrations of medical devices include the following:autotransfusion devices, blood filters, blood pumps, blood temperaturemonitors, bone growth stimulators, breathing circuit connectors, bulldogclamps, cannulae, grafts, implantible pumps, impotence and incontinenceimplants, intra-ocular lenses, leads, lead adapters, lead connectors,nasal buttons, orbital implants, cardiac insulation pads, cardiacjackets, clips, covers, dialators, dialyzers, disposable temperatureprobes, domes, drainage products, drapes, ear wicks, electrodes, embolicdevices, esophageal stethoscopes, fracture fixation devices, gloves,guide wires, hemofiltration devices, hubs, intra-arterial blood gassensors, intracardiac suction devices, intrauterine pressure devices,nasal spetal splints, nasal tampons, needles, ophthalmic devices, PAPbrushes, periodontal fiber adhesives, pessary, retention cuffs,sheeting, staples, stomach ports, surgical instruments, transducerprotectors, ureteral stents, vaginal contraceptives, valves, vesselloops, water and saline bubbles, acetabular cups, annuloplasty ring,aortic/coronary locators, artificial pancreas, batteries, bone cement,breast implants, cardiac materials, such as fabrics, felts, mesh,patches, cement spacers, cochlear implant, defibrillators, generators,orthopedic implants, pacemakers, patellar buttons, penile implant,pledgets, plugs, ports, prosthetic heart valves, sheeting, shunts,umbilical tape, valved conduits, and vascular access devices.

Generally, a solution of the copolymer is prepared at a concentration ofabout 1% to a concentration of about 10% in water or an aqueous buffersolution. Depending on the surface being coated, an organic solvent suchas isopropyl alcohol (“IPA”) can be included in the solution atconcentrations varying from about 1 to about 40%. The medical device orsurface to be coated can be dipped into the copolymer solution, or,alternatively, the copolymer solution can be applied to the surface ofthe device by spraying or the like. At this point, the device can beair-dried to evaporate the solvent or can proceed to the illuminationstep without drying. The devices can be rotated and illuminated with UVlight for 5–10 minutes to insure an even coat of the coating. Thisprocess can be repeated multiple times to attain the desired coatingthickness. Coating thicknesses can be evaluated using scanning electronmicroscopy (SEM) in both the dry and hydrated forms. The difference inthickness between the dry and the hydrated condition is not generallysignificant. The thickness of the coating ranges from about 0.5 micronsto about 20 microns and preferably from about 2 microns to about 10microns.

If a significant amount of surface area is to be coated, it may bepreferable to place the device in a rotating fixture to facilitate thecoverage of the device's surface. For example, to coat the entiresurface of a vascular stent, the ends of the device are fastened to arotating fixture by resilient retainers, such as alligator clips. Thestent is rotated in a substantially horizontal plane around its axis.The spray nozzle of the airbrush is typically placed 2–4 inches from thedevice. The thickness of the coating can be adjusted by the speed ofrotation and the flow rate of the spray nozzle.

Medicament is typically incorporated into the matrix after the matrixitself has been coated onto a medical device. Generally a solution ofmedicament or medicaments is prepared and the matrix-coated device issoaked in the solution. Medicament is absorbed into the matrix from thesolution. Various solvents can be used to form the medicament solutionas the amount of medicament absorbed by the matrix can be controlled bythe solvent solution. Likewise, the pH and/or the ionic strength of themedicament solution can be adjusted to control the degree of medicamentabsorption by the matrix. After soaking in medicament solution for aperiod of time, the medical device is removed and air dried.

A coating of the present invention is preferably sufficiently durableand tenacious to permit the coating to remain on the device surface, invivo, for a period of time sufficient for its intended use, includingthe delivery of medicaments. The durability and/or tenacity of variouscoatings, on various surfaces, can be assessed using conventionaltechniques.

Applicants, for instance, have constructed a device that includes theuse of an adjustable O-ring connected to a high-end torque screw-driver.Using this device it is possible to place a constant and replicableforce on a coated medical device, e.g., a catheter. The coated medicaldevice to be tested is inserted into the O-ring and the torque appliedto a desired level. The coated device is pulled through the device apredetermined number of times. The coated device is then removed fromthe O-ring and the device evaluated to determine the amount of matrixremaining on the surface. The matrix remaining on the surface can bedetected either directly, e.g., by staining, and/or indirectly, e.g.,using a drug loading and release assay. After 5 cycles through thedevice described above, a medical device coated with a formulation ofthe present invention, preferably retains the ability to absorb andrelease at least 75% of its initial capacity.

Other suitable biomaterials include those substances that do not possessabstractable hydrogens to which the photogroups can form covalent bonds.Such biomaterials can be used in a variety of ways. For instance,biomaterials can be made suitable for coating via photochemistry byapplying a suitable primer coating which bonds to the biomaterialsurface and provides a suitable substrate for binding by thephotogroups. For instance, metals and ceramics having oxide groups ontheir surfaces can be made suitable for coupling via photochemistry byadding a primer coating that binds to the oxide groups and providesabstractable hydrogens. Such metals include, but are not limited to,titanium, stainless steel, and cobalt chromium, while such ceramics caninclude, but are not limited to, silicon nitride, silicon carbide,zirconia, and alumina, as well as glass, silica, and sapphire. Onesuitable class of primers for metals and ceramics are organosilanereagents, which bond to the oxide surface and provide hydrocarbon groups(Brzoska, J. B., et. al., Langmuir 10:4367–4373, 1994). This referenceteaches that —SiH groups are suitable alternatives for bonding ofphotogroups.

Similarly, various tie layers can be applied to various metals, glass,and ceramics, which can in turn serve as sources of abstractablehydrogens for photochemical coupling to the surface. Various polymericmaterials such as Nylon, polystyrene, polyurethane, polyethyleneterepthalate, and various monomeric analogs used to prepare suchpolymers could be used for such tie layers. See, for instance, U.S. Pat.Nos. 5,443,455; 5,749,837; 5,769,796; 5,997,517.

The present invention further includes the optional use of additional,e.g., “clad”, layers covering and/or between layers of the compositionin either a continuous or discontinuous fashion. For instance, one ormore outer layers of one or more other materials, e.g., a hydrophilic orprotective outer coating, can be photoimmobilized or otherwise bound,absorbed or attached on or to a coating prepared as described herein.

If desired, for instance, such an additional coating can be applied ontop of a medicament absorbing layer, either before and/or aftermedicament has been absorbed into the matrix. It is preferable to addthe additional layer before medicament has been absorbed. For instance,a solution of the same or of a different copolymer can be prepared andthe coated device dipped, sprayed or otherwise contacted with thesolution and illuminated as described previously. The coated device canthen be contacted with, e.g., soaked in, the medicament solution asdescribed previously. Medicament will pass through the top coat and beabsorbed by the underlying matrix. When placed in the body, themedicament will be released as described herein. Using such a method, acoating with enhanced lubricity, hemocompatibility, or other desiredproperty can be incorporated into the medical device surface, thusforming a device coating that provides multiple desired properties.

The invention will be further described with reference to the followingnon-limiting examples.

EXAMPLES Example 1 Preparation of 4-Benzoylbenzoyl Chloride (BBA-Cl)(Compound I)

4-Benzoylbenzoic acid (BBA), 1.0 kg (4.42 moles), was added to a dry 5liter Morton flask equipped with reflux condenser and overhead stirrer,followed by the addition of 645 ml (8.84 moles) of thionyl chloride and725 ml of toluene. Dimethylformamide, 3.5 ml, was then added and themixture was heated at reflux for 4 hours. After cooling, the solventswere removed under reduced pressure and the residual thionyl chloridewas removed by three evaporations using 3×500 ml of toluene. The productwas recrystallized from 1:4 toluene:hexane to give 988 g (91% yield)after drying in a vacuum oven. Product melting point was 92–94° C.Nuclear magnetic resonance (“NMR”) analysis at 80 MHz (¹H NMR (CDCl₃))was consistent with the desired product: aromatic protons 7.20–8.25 (m,9H). All chemical shift values are in ppm downfield from atetramethylsilane internal standard. The final compound (Compound Ishown below) was stored for use in the preparation of a monomer used inthe synthesis of photoactivatable polymers as described, for instance,in Example 3.

Example 2 Preparation of N-(3-Aminopropyl)methacrylamide Hydrochloride(APMA) (Compound II)

A solution of 1,3-diaminopropane, 1910 g (25.77 moles), in 1000 ml ofCH₂Cl₂ was added to a 12 liter Morton flask and cooled on an ice bath. Asolution of t-butyl phenyl carbonate, 1000 g (5.15 moles), in 250 ml ofCH₂Cl₂ was then added dropwise at a rate which kept the reactiontemperature below 15° C. Following the addition, the mixture was warmedto room temperature and stirred 2 hours. The reaction mixture wasdiluted with 900 ml of CH₂Cl₂ and 500 g of ice, followed by the slowaddition of 2500 ml of 2.2 N NaOH. After testing to insure the solutionwas basic, the product was transferred to a separatory funnel and theorganic layer was removed and set aside as extract #1. The aqueous wasthen extracted with 3×1250 ml of CH₂Cl₂, keeping each extraction as aseparate fraction. The four organic extracts were then washedsuccessively with a single 1250 ml portion of 0.6 N NaOH beginning withfraction #1 and proceeding through fraction #4. This wash procedure wasrepeated a second time with a fresh 1250 ml portion of 0.6 N NaOH. Theorganic extracts were then combined and dried over Na₂SO₄. Filtrationand evaporation of solvent to a constant weight gave 825 g ofN-mono-t-BOC-1,3-diaminopropane which was used without furtherpurification.

A solution of methacrylic anhydride, 806 g (5.23 moles), in 1020 ml ofCHCl₃ was placed in a 12 liter Morton flask equipped with overheadstirrer and cooled on an ice bath. Phenothiazine, 60 mg, was added as aninhibitor, followed by the dropwise addition ofN-mono-t-BOC-1,3-diaminopropane, 825 g (4.73 moles), in 825 ml of CHCl₃.The rate of addition was controlled to keep the reaction temperaturebelow 10° C. at all times. After the addition was complete, the ice bathwas removed and the mixture was left to stir overnight. The product wasdiluted with 2400 ml of water and transferred to a separatory funnel.After thorough mixing, the aqueous layer was removed and the organiclayer was washed with 2400 ml of 2 N NaOH, insuring that the aqueouslayer was basic. The organic layer was then dried over Na₂SO₄ andfiltered to remove drying agent. A portion of the CHCl₃ solvent wasremoved under reduced pressure until the combined weight of the productand solvent was approximately 3000 g. The desired product was thenprecipitated by slow addition of 11.0 liters of hexane to the stirredCHCl₃ solution, followed by overnight storage at 4° C. The product wasisolated by filtration and the solid was rinsed twice with a solventcombination of 900 ml of hexane and 150 ml of CHCl₃. Thorough drying ofthe solid gave 900 g ofN-[N′-(t-butyloxycarbonyl)-3-aminopropyl]-methacrylamide, m.p. 85.8° C.by differential scanning calorimetry (“DSC”). Analysis on an NMRspectrometer was consistent with the desired product: ¹H NMR (CDCl₃)amide NH's 6.30–6.80, 4.55–5.10 (m, 2H), vinyl protons 5.65, 5.20 (m,2H), methylenes adjacent to N 2.90–3.45 (m, 4H), methyl 1.95 (m, 3H),remaining methylene 1.50–1.90 (m, 2H), and t-butyl 1.40 (s, 9H).

A 3-neck, 2 liter round bottom flask was equipped with an overheadstirrer and gas sparge tube. Methanol, 700 ml, was added to the flaskand cooled on an ice bath. While stirring, HCl gas was bubbled into thesolvent at a rate of approximately 5 liters/minute for a total of 40minutes. The molarity of the final HCl/MeOH solution was determined tobe 8.5 M by titration with 1 N NaOH using phenolphthalein as anindicator. The N-[N′-(t-butyloxycarbonyl)-3-aminopropyl]methacrylamide,900 g (3.71 moles), was added to a 5 liter Morton flask equipped with anoverhead stirrer and gas outlet adapter, followed by the addition of1150 ml of methanol solvent. Some solids remained in the flask with thissolvent volume. Phenothiazine, 30 mg, was added as an inhibitor,followed by the addition of 655 ml (5.57 moles) of the 8.5 M HCl/MeOHsolution. The solids slowly dissolved with the evolution of gas but thereaction was not exothermic. The mixture was stirred overnight at roomtemperature to insure complete reaction. Any solids were then removed byfiltration and an additional 30 mg of phenothiazine were added. Thesolvent was then stripped under reduced pressure and the resulting solidresidue was azeotroped with 3×1000 ml of isopropanol with evaporationunder reduced pressure. Finally, the product was dissolved in 2000 ml ofrefluxing isopropanol and 4000 ml of ethyl acetate were added slowlywith stirring. The mixture was allowed to cool slowly and was stored at4° C. overnight. Compound II was isolated by filtration and was dried toconstant weight, giving a yield of 630 g with a melting point of 124.7°C. by DSC. Analysis on an NMR spectrometer was consistent with thedesired product: ¹H NMR (D₂O) vinyl protons 5.60, 5.30 (m, 2H),methylene adjacent to amide N 3.30 (t, 2H), methylene adjacent to amineN 2.95 (t, 2H), methyl 1.90 (m, 3H), and remaining methylene 1.65–2.10(m, 2H). The final compound (Compound II shown below) was stored for usein the preparation of a monomer used in the synthesis ofphotoactivatable polymers as described, for instance, in Example 3.

Example 3 Preparation of N-[3-(4-Benzoylbenzamido)propyl]methacrylamide(BBA-APMA) (Compound III)

Compound II 120 g (0.672 moles), prepared according to the generalmethod described in Example 2, was added to a dry 2 liter, three-neckround bottom flask equipped with an overhead stirrer. Phenothiazine,23–25 mg, was added as an inhibitor, followed by 800 ml of chloroform.The suspension was cooled below 10° C. on an ice bath and 172.5 g (0.705moles) of Compound I, prepared according to the general method describedin Example 1, were added as a solid. Triethylamine, 207 ml (1.485moles), in 50 ml of chloroform was then added dropwise over a 1–1.5 hourtime period. The ice bath was removed and stirring at ambienttemperature was continued for 2.5 hours. The product was then washedwith 600 ml of 0.3 N HCl and 2×300 ml of 0.07 N HCl. After drying oversodium sulfate, the chloroform was removed under reduced pressure andthe product was recrystallized twice from 4:1 toluene:chloroform using23–25 mg of phenothiazine in each recrystallization to preventpolymerization. Typical yields of Compound III were 90% with a meltingpoint of 147–151° C. Analysis on an NMR spectrometer was consistent withthe desired product: ¹H NMR (CDCl₃) aromatic protons 7.20–7.95 (m, 9H),amide NH 6.55 (broad t, 1H), vinyl protons 5.65, 5.25 (m, 2H),methylenes adjacent to amide N's 3.20–3.60 (m, 4H), methyl 1.95 (s, 3H),and remaining methylene 1.50–2.00 (m, 2H). The final compound (CompoundIII shown below) was stored for use in the synthesis of photoactivatablepolymers as described in Examples 4 and 5.

Example 4 Preparation of Polyacrylamide(36%)co-Methacrylicacid(MA)-(10%)co-Methoxy PEG1000MA-(4%)co-BBA-APMA (Compound IV)

Acrylamide, 39.3 g (0.55 mole), and BBA-APMA (Compound III), 15.5 g(0.04 mole), were dissolved in dimethylsulfoxide (“DMSO”), followed bymethoxypolyethyleneglycol 1000 monomethacrylate (methoxy PEG 1000 MA),110.8 g (0.11 mole), methacrylic acid, 33.8 ml (0.4 mole),2,2′-azobisisobutyronitrile (“AIBN”), 2.3 g (0.01 mole), andN,N,N′,N′,-tetramethylethylenediamine (“TEMED”), 2.2 ml (0.02 mole). Thesolution was deoxygenated with a helium sparge for 60 minutes at 60° C.,then sealed under argon and heated overnight at 60° C. The resultingproduct was dialyzed against deionized water using 12,000–14,000molecular weight cutoff tubing for 66 to 96 hours, then filtered throughWhatman #1 filter paper before being lyophilized to give 190 g ofpolymer. The resultant polymer was identified as methacrylicacid-co-methoxy PEG1000-MA-co-BBA-APMA having the following generalstructure (Compound IV).

Example 5 Preparation of Various Analogs of Compound (IV)

A series of polymers of the general formula of Compound IV weresynthesized as generally described in Example 4. The mole percent ofacrylamide and methoxy PEG1000 monomethacrylate were varied while themole percent of the BBA-APMA (Compound III) was constant at four molepercent. The ratios of the other groups to carbonyl groups in thevarious polymers were calculated assuming each mole of the methoxyPEG1000 monomethacrylate contained 23 ether groups. A list of thevarious polymers prepared and the composition of the various polymersare listed below.

The following compounds were synthesized in a manner analogous to thatdescribed above with respect to Compound IV.

-   2. 4% BBA-APMA, 10% methoxy PEG1000 monomethacrylate, 86%    Methacrylic acid (Polymer #8 in table below)-   3. 4% BBA-APMA, 2% methoxy PEG1000 monomethacrylate, 66% Acrylamide,    28% Methacrylic acid (Polymer #1 in table below)-   4. 4% BBA-APMA, 2% methoxy PEG1000 monomethacrylate, 42% Acrylamide,    52% Methacrylic acid (Polymer #2 in table below)-   5. 4% BBA-APMA, 26% methoxy PEG1000 monomethacrylate, 42%    Acrylamide, 28% Methacrylic acid (Polymer #3 in table below)-   6. 4% BBA-APMA, 2% methoxy PEG1000 monomethacrylate, 54% Acrylamide,    40% Methacrylic acid (Polymer #4 in table below)-   7. 4% BBA-APMA, 14% methoxy PEG1000 monomethacrylate, 54%    Acrylamide, 28% Methacrylic acid (Polymer #5 in table below)-   8. 4% BBA-APMA, 14% methoxy PEG1000 monomethacrylate, 42%    Acrylamide, 40% Methacrylic acid (Polymer #6 in table below)-   9. 4% BBA-APMA, 2% methoxy PEG1000 monomethacrylate, 42% Acrylamide,    52% Methacrylic acid-   10. 4% BBA-APMA, 60% Acrylamide, 36% Methacrylic acid-   11. 4% BBA-APMA, 50% Acrylamide, 46% Methacrylic acid-   12. 4% BBA-APMA, 40% Acrylamide, 56% Methacrylic acid

The mole % BBA-APMA was constant at 4 mole %. The ratios of ether groupsto carboxyl groups in the various polymers were calculated assuming eachmole of methoxy PEG1000 monomethacrylate contained 100/44=23 ethergroups. The composition of the various polymers were:

Mole % Mole % Mole % Methacrylic Ratio Polymer # Acrylamide MeO—PEG AcidO/COOH 1 66  2 28 1.64 2 42  2 52 0.88 3 42 26 28 21.4** 4 54  2 40 1.155 54 14 28 11.5** 6 42 14 40 8.05** 7 50 10 36 6.39 (Compound IV) 8 8610  0 Undefined **Polymers #3, #5, and #6 were poorly soluble in waterand difficult to coat.

Example 6 Release of Chlorhexidine Diacetate and Hexachlorophene onStainless Steel Rods Tested Against Staphylococcus epidermidis

Stainless steel (SS, 304) rods (0.75 in., 2 cm) were initiallypretreated with Parylene C as follow: First, the rods were cleaned withEnprep 160SE detergent (Ethone-OMI Inc., Bridgeview, Ill.) followed bysilylation with γ-methacryoxypropyltrimethoxysilane (Sigma Chemical Co.,St. Louis, Mo.). Five grams of Parylene C (Specialty Coating Systems,Indianapolis, Ind.) was loaded into the vaporizer of a Labcoter 1,Parylene Deposition Unit, Model PDS 2010 (Specialty Coating Systems,Indianapolis, Ind.) and the parylene was deposited onto the rods inorder to achieve a uniform and durable coating of the desired thickness.After precoating, the rods were wiped clean with a cloth soaked inisopropyl alcohol (IPA). A solution of Compound IV was prepared at aconcentration of 50 mg/ml in 20% IPA. The rods were dipped at 1.0 cm(0.4 in.)/sec into and 0.5 cm (0.2 in.)/sec out of solution (with nodwell period for the first application and a 30 sec dwell period for thesecond application). After air-drying for approximately 20 minutes, thecoated rods were suspended midway between opposed ELC 4000 lamps (40 cm(15.7 in) apart) containing 400 watt mercury vapor bulbs which put out1.5 mW/sq. cm from 330–340 nm at the point of illumination. The rodswere rotated and illuminated for five minutes to insure an even coat ofthe coating. Two coats were applied.

Two separate solutions of chlorhexidine and hexachlorophene wereprepared. Chlorhexidine diacetate (“CDA”) (100 mg/ml) was dissolved in70% ethanol (EtOH) and hexachlorophene (“HCP”) was also dissolved in 70%EtOH by heating. The SS rods coated with Compound IV were incubated witheither the CHA or HCP solution for 30 minutes at room temperature. Theparts were air-dried overnight.

The longevity of the antiseptic release was evaluated by transferringthe rods from one agar surface to a fresh agar surface for zone ofinhibition analysis. Basically, the 2 cm (0.8 in.) SS rods were laidparallel on to a Mueller-Hinton agar surface that was incubated withapproximately a 1×10⁶ CFU/ml of Staphylococcus epidermidis (ATCC 35984).The agar plates containing the parts were incubated overnight at 37° C.The zones of inhibition or areas of no bacterial growth were measuredacross the diameter of the part. Samples were transferred daily to newagar plates with fresh lawns of S. epidermidis until no zones ofinhibition were present.

The CDA containing rods produced zones starting at approximately 34 mmand leveling off to 15–18 mm by day 4 and continued at that size throughday 14 while the HCP containing parts produced zones starting atapproximately 33 mm and leveling off to 30 mm by day 3 and continued atthat size through day 14 (end of experiment).

Example 7 Release of Chlorhexidine Digluconate (“CHG”) on StainlessSteel Rods Tested Against Staphylococcus epidermidis, Staphylococcusaureus, Escherichia coli, and Candida albicans

Stainless steel (SS, 304) rods (0.75 in., 2 cm) were pretreated and asolution of compound W was prepared as described in Example 6. A portionof the rods (0.6 in., 1.6 cm) was dip-coated into the coating solutionby dipping into the solution at 0.5 cm (0.2 in.)/sec, swelling for 30seconds and withdrawing at a rate of 0.2 cm (0.08 in.)/sec for the first1.2 cm (0.5 in.) of the rod, the reduced to 0.05 cm (0.02 in.) for thelast 0.4 cm (0.16 in.) of the rod. The rods were air-dried for 15minutes and UV illuminated for 5 minutes with rotation as described inExample 6. Two coats were applied.

Chlorhexidine digluconate (CHG) (100 mg/ml) was diluted further indeionized (DI) water. Compound IV-coated parylene treated and uncoatedrods were sterilized for 20 minutes in 70% IPA and air-dried. All of therods were soaked for one hour at room temperature in the CHG solution.The parts were then air-dried overnight.

The CHG-incorporated parts as well as uncoated and Compound-IV coatedwithout CHG were tested in the zone of inhibition assay agent S.epidermidis (ATCC 35984), S. aureus (ATCC 25923) E. coli (ATCC 25922)and C. albicans (ATCC 10231) as described in Example 6.

The following results were obtained. S. epidermidis: The controls forboth the uncoated and Compound IV-coated did not produce zones. Theuncoated parts with CHG produced zones starting at 22 mm on day 1 anddropped off to no zones by day 4. The parylene-only coated samples withdrug gave zones starting at 25 mm and dropped off to zero zones by day5. The Compound IV-coated samples with CHG incorporated had zonesstarting at 25 mm, which leveled off to 15–20 mm by day 2 through day14, and decreasing to 5 mm by day 21. E. coli: The controls with no drugfor both uncoated and Compound IV-coated did not produce zones. Theuncoated parts with CHG produced zones starting at 15 mm and dropped offwith no zones by 4 days. The parylene-only sample with drug gave zonesstarting at 22 mm and dropped off to no zones by 5 days. The CompoundIV-coated samples with drug had zones starting at 20 mm and graduallydecreased to no zones by day 21. C. albicans: The controls with no drugfor both uncoated and Compound IV-coated produced no zones. The uncoatedparts with CHG produced zones starting at 17 mm for day one only. Theparylene-only samples with drug gave zones starting at 19 mm and lastedonly 2 days. The Compound IV-coated samples with drug gave zones thatstarted at 28 mm and gradually decreased to zero zones by day 18. S.aureus: The controls with no drug for both uncoated and CompoundIV-coated did not produce zones. The uncoated parts with CHG producedzones starting at 23 and dropped off to no zones by day 4. Theparylene-only samples with drug gave zones starting at 25 mm and droppedoff to no zones by day 3. The Compound TV-coated samples with drug hadzones starting at 23 mm and gradually decreased to 13 mm through day 12.On day 13 the study was discontinued due to contamination.

Example 8 Release of Chlorhexidine Digluconate (CHG) on Titanium RodsTested Against S. epidermidis, S. aureus, E. coli, and C. albicans

Titanium (90 Ti/6 Al/4V) rods (0.75 in., 2 cm) were pretreated withparylene and a Compound IV solution was prepared as described in Example6. The rods were dip coated as described in Example 7, except that theentire rod was coated. The rods were air-dried and UV cured as describedin Example 6. Two coats were applied.

The uncoated, parylene treated, and Compound IV-coated rods weresterilized in 70% IPA for 20 minutes and air-dried. The samples werethen incorporated with CHG at 100 mg/ml in DI water for one hour at roomtemperature with agitation. The rods were rinsed by dipping three timesinto tubes containing DI water and air-dried overnight.

The quantity of CHG eluted from the rods was also determined. Theindividual rods were placed into test tubes containing 2 ml of PhosphateBuffer Saline (“PBS”) and were incubated at 37° C. overnight withagitation. The rods were transferred to fresh PBS daily, and the eluateswere diluted into the High Pressure Liquid Chromatography (HPLC) mobilephase to solubilize the CHG. The amount of CHG eluted was measured byHPLC and was determined to be 12.3 μg/rod for uncoated, 10.1 μg/rod forparylene-only, and 275 μg/rod for Compound IV-coated.

Also the CHG incorporated parts, as well as uncoated and CompoundIV-coated without CHG were tested in the zone of inhibition assayagainst S. epidermidis (ATCC 35984), S. aureus (ATCC 25923) E. coli(ATCC 25922) and C. albicans (ATCC 10231) as described in Example 6. Theresults were as follows: S. epidermidis: The uncoated and parylene-onlygave zone of 15–18 mm on day 1 and died off by day 3. The CompoundIV-coated rods with drug gave zones starting at 24 mm, leveling at 15–19mm from day 2–21 and then gradually decreasing to no zone on day 27. S.aureus: The uncoated and parylene-only gave zone of 14–16 mm on day 1and dropped off to no zones by day 3. The Compound IV samples with druggave zones starting at 20 mm and gradually decreasing to 12 mm on day16. They were discontinued on day 20 due to contamination. E. coli:Uncoated and parylene-only gave zones of 13–14 mm on day 1 and droppedoff to no zones by day 3. The Compound IV sample with drug gave zonesstarting at 20 mm and gradually decreased to no zones on day 20. C.albicans: Uncoated and parylene-only gave zone of 7–10 mm on day 1 anddropped off to no zone by day 2. The Compound IV samples with drug hadzones starting at 19 mm and gradually decreased to no zones on day 21.

Example 9 Release of Benzalkonuim Chloride (“BAK”) and CHG from Pebax™Rods Tested Against S. epidermidis and E. coli

Pebax™ rods (0.75 in., 2 cm) were wiped clean with an EPA soaked clothand a Compound IV solution was prepared as described in Example 6. Therods were dipped at 3.0 cm (1.2 in.)/sec into, 30 sec dwell, and a 3.0cm (1.2 in.)/sec out of solution. The rods were air-dried forapproximately ten minutes and UV illuminated for 3 minutes with rotationas described in Example 6. Two coats were applied and a portion of thePebax™ rods were cut into 1 cm (0.4 in.) pieces for the zone ofinhibition testing.

BAK and CHG were prepared at 100 mg/ml in DI water and the samples wereincorporated for one hour at room temperature with agitation. The rodswere rinsed three times in DI water and air-dried overnight.

The samples were tested in the zone of inhibition assay against S.epidermidis (ATCC 35984) and E. coli (ATCC 25922) as described inExample 6 except the rods were placed perpendicular into the agar. S.epidermidis results: The Compound IV coatings containing BAK gave zonesstarting at 26 mm and gradually decreasing to no zones by day 16. TheCHG coated rods gave zones that started at 22 mm and gradually decreasedto 12 mm on day 16 when the study was discontinued. E. coli : The BAKcoated rods gave zones that started at 11 mm but lasted only 2 days. TheCHG coated rods gave zones that started at 15 mm and gradually decreasedto 9 mm on day 16 when the study was discontinued.

Example 10 Release of CHG form Polyurethane (Pellethane) CatheterMaterial Tested Against S. epidermidis

The polyurethane (PU) catheter material was wiped clean with IPA and asolution of Compound IV for coating was prepared as described in Example6. The rods were dip coated in the coating solution by dipping into thesolution at 1.0 cm (0.4 in.)/sec, dwelling for 30 seconds, andwithdrawing at a rate of 0.5 cm (0.2 in.)/sec. The rods were air-driedfor 15 minutes and UV illuminated for three minutes with rotation asdescribed in Example 6. Two coats of the Compound IV coating wereapplied.

The Compound IV coated rods were wiped with 70% IPA and dried for onehour. The rods were cut into 2 cm lengths and the CHG was incorporatedby dipping the rods into a 200 mg/ml solution of CHG for one hour atroom temperature and then rinsed three times in DI water. The sampleswere air-dried overnight and tested in the zone of inhibition assayagainst S. epidermidis (ATCC25984) as described in Example 6.

All of the uncoated samples and coated samples containing no drugproduced no zones of inhibition. The Compound IV-coated zones with drugstarted at 28 mm at day zero and gradually decreased to no zones on day23.

Example 11 Release of Alexidine Dihydrochloride (“ADC”) fromPolyurethane Rods Tested Against S. epidermidis

Polyurethane rods (6 in., 15 cm) were wiped clean as described inExample 9 and a Compound IV solution was prepared as in Example 6. Therods were dip-coated by dipping into the solution at a rate of 2.0 cm(0.8 in.)/sec, dwelling for 30 seconds and withdrawing at 3.0 (1.2in.)/sec. The samples were air-dried for 10 minutes and UV illuminatedfor two minutes with rotation as described in Example 6. Two coats wereapplied.

A solution of alexidine dihydrochloride (ADC) (100 mg/ml) in 50%methanol was prepared with heat. The PU rods were cut into 1 cm lengthsand incorporated with the alexidine in the ADC solution in a warm waterbath. The rods were incorporated for one hour, rinsed three times in DIwater, and air-dried over night. The samples were tested in the zone ofinhibition against S. epidermidis (ATCC 35984) as described in Example6.

All of the uncoated samples and coated samples containing no drugproduced no zones of inhibition. The Compound IV-coated zones withalexidine started at 12 mm and leveled off at 6–9 mm form day 2 throughthe duration of the test period of 21 days.

Example 12 Release of Vancomycin (“VA”) on Coated PU Rods Tested AgainstS. epidermidis

Polyurethane rods (6 in., 15 cm) were wiped clean as described inExample 9 and a Compound IV solution was prepared as in Example 6. Therods were dip coated in the coating solution by dipping into thesolution at 2.0 cm (0.8 in.)/sec, dwelling for 30 seconds, andwithdrawing at 2.0 (0.8 in.)/sec. The rods were air-dried for 15 minutesand UV illuminated for four minutes with rotation as described inExample 6. Two coats were applied.

A solution of vancomycin (VA) was prepared at 50 mg/ml in DI water. Therods were incorporated with VA in the VA solution for one hour at roomtemperature, rinsed three times in DI water, air-dried, and cut into 1cm pieces. The samples were tested against S. epidermidis (ATCC35984) asdescribed in Example 6.

All of the uncoated samples and coated samples containing no drugproduced no zones of inhibition. The Compound IV coated zones with VAstarted at 20 mm and dropped off to no zones by day 6.

1. A method of preparing a crosslinked coating composition for use indelivering a medicament from the surface of a medical device whenpositioned in vivo, the method comprising the steps of: 1) providing apolymeric reagent formed by the polymerization of the followingmonomers: a) about 1 to about 20 mole % of a polyether monomer, b) about5 to about 75 mole % of a carboxylic acid-containing monomer, such thatthe effective ratio of ether groups to carboxylic acid groups in theresultant copolymer is between about 1 to 1 and about 10 to 1, c)optionally, about 0.1 to about 10 mole % of a photoderivatized monomer,and d) an amount of a hydrophilic monomer suitable to bring thecomposition to 100%, 2) applying the composition as a coating to thesurface of the medical device under conditions suitable to form a gelmatrix by a process that includes a complexation reaction betweencarboxylic acid groups and ether groups, and 3) incorporating amedicament into the composition.
 2. A method according to claim 1wherein the polyether monomer comprises an alkoxy (poly)alkyleneglycol(meth)acrylate.
 3. A method according to claim 2 wherein the alkoxygroup is selected from the group consisting of methoxy, ethoxy, propoxy,and butoxy.
 4. A method according to claim 2 wherein the (poly)alkyleneglycol component of the alkoxy (poly)alkyleneglycol (meth)acrylate isselected from the group consisting of (poly)propylene glycol and(poly)ethylene glycol.
 5. A method according to claim 4 wherein the(poly)alkylene glycol has a nominal weight average molecular weightranging from about 200 g/mole to about 2000 g/mole.
 6. A methodaccording to claim 5 wherein the polyether monomer is selected from thegroup consisting essentially of methoxy (poly)ethylene glycolmethacrylates, (poly)ethylene glycol methacrylates, and (poly)propyleneglycol methacrylates.
 7. A method according to claim 1 wherein thepolyether monomer is present in an amount of between about 5 and about15 mole %.
 8. A method according to claim 1 wherein the carboxylicacid-containing monomer is selected from carboxyl substituted ethylenecompounds.
 9. A method according to claim 8 wherein the carboxylacid-containing monomer is selected from acrylic, methacrylic, maleic,crotonic, itaconic, and citraconic acid.
 10. A method according to claim8 wherein the carboxyl acid-containing monomer is present at aconcentration of about 5 to about 75 mole %, such that the effectiveratio of ether groups to carboxylic acid groups in the resultantcopolymer is between about 1 to 1 and about 10 to
 1. 11. A methodaccording to claim 10 wherein the concentration of the carboxylicacid-containing monomer is between about 30 to about 50 mole %.
 12. Amethod according to claim 9 wherein the carboxylic-acid containingmonomer comprises (meth)acrylic acid.
 13. A method according to claim 1wherein the photoderivatized monomer is selected from the groupconsisting of N-[3-(4-benzoylbenzoamido)propyl]methacrylamide, 9-vinylanthracene, and 9-anthracenylmethyl methacrylate.
 14. A method accordingto claim 13 wherein the photoderivatized monomer is present in an amountof between about 1 to about 7 mole %.
 15. A method according to claim 1wherein the hydrophilic monomer comprises an alkenyl substituted amide.16. A method according to claim 15 wherein the hydrophilic monomer isselected from the group consisting of acrylamide, N-vinylpyrrolidone,methacrylamide, and acrylamido propanesulfonic acid (AMPS).
 17. A methodaccording to claim 16 wherein the hydrophilic monomer is present in anamount of between about 30 and about 70 mole %.
 18. A method accordingto claim 1 wherein the medicament is selected from the group consistingof peptides, proteins, carbohydrates, nucleic acids, lipids,polysaccharides and combinations thereof.
 19. A method according toclaim 1 wherein the medicament is selected from the group consisting ofgene therapy agents selected from therapeutic nucleic acids and nucleicacids encoding therapeutic gene products, antibiotics selected frompenicillin, tetracycline, chloramphenicol, minocycline, doxycycline,vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromycinand cephalosporins and antiseptics selected from silver sulfadiazine,chlorhexidine, glutaraldehyde, peracetic acid, sodium hypochlorite,phenols, phenolic compounds, iodophor compounds, quaternary ammoniumcompounds, and chlorine compounds.
 20. A method according to claim 1wherein the device is selected from the group consisting of catheters,implantable vascular access ports, blood storage bags, vascular stents,blood tubing, central venous catheters, arterial catheters, vasculargrafts, intraaortic balloon pumps, heart valves, cardiovascular sutures,total artificial hearts and ventricular assist pumps, extracorporealdevices such as blood oxygenators, blood filters, hemodialysis units,hemoperfusion units, plasmapheresis units, hybrid artificial organs suchas pancreas or liver and artificial lungs and filters adapted fordeployment in a blood vessel in order to trap emboli.
 21. A methodaccording to claim 1 wherein the medicament is incorporated into thecomposition prior to applying the composition to the surface.
 22. Amethod according to claim 1 wherein the medicament is incorporated intothe composition after applying the composition to the surface.
 23. Amethod according to claim 20 wherein the medical device is prepared frompolymeric, metallic, or ceramic material and combinations thereof.
 24. Amethod according to claim 21, wherein the device provides a polymericsurface selected from the group consisting of polyurethane and itscopolymers, silicone and its copolymers, ethylene vinyl-acetate,thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics,polyamides, polyesters, polysulfones, polytetrafluorethylenes,polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics,polylactic acid, polyglycolic acid, polycaprolactone, polylacticacid-polyethylene oxide copolymers, cellulose, collagens, and chitins.25. A method according to claim 1 wherein the polyether monomercomprises an alkoxy (poly)alkyleneglycol (meth)acrylate, the carboxylicacid-containing monomer is selected from carboxyl substituted ethylenecompounds, the photoderivatized monomer is selected from the groupconsisting of N-[3-(4-benzoylbenzoamido)propyl]methacrylamide, 9-vinylanthracene, and 9-anthracenylmethyl methacrylate, and the hydrophilicmonomer is selected from the group consisting of acrylamide,N-vinylpyrrolidone, methacrylamide, and acrylamido propanesulfonic acid(AMPS).
 26. A method according to claim 25 wherein the medicament isselected from the group consisting of gene therapy agents selected fromtherapeutic nucleic acids and nucleic acids encoding therapeutic geneproducts, antibiotics selected from penicillin, tetracycline,chloramphenicol, minocycline, doxycycline, vancomycin, bacitracin,kanamycin, neomycin, gentamycin, erythromycin and cephalosporins andantiseptics selected from silver sulfadiazine, chlorhexidine,glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenoliccompounds, iodophor compounds, quaternary ammonium compounds, andchlorine compounds and the device is selected from the group consistingof catheters, implantable vascular access ports, blood storage bags,vascular stents, blood tubing, central venous catheters, arterialcatheters, vascular grafts, intraaortic balloon pumps, heart valves,cardiovascular sutures, total artificial hearts and ventricular assistpumps, extracorporeal devices such as blood oxygenators, blood filters,hemodialysis units, hemoperfusion units, plasmapheresis units, hybridartificial organs such as pancreas or liver and artificial lungs andfilters adapted for deployment in a blood vessel in order to trapemboli.
 27. A method according to claim 25, wherein the device providesa polymeric surface selected from the group consisting of polyurethaneand its copolymers, silicone and its copolymers, ethylene vinyl-acetate,thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics,polyamides, polyesters, polysulfones, polytetrafluorethylenes,polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics,polylactic acid, polyglycolic acid, polycaprolactone, polylacticacid-polyethylene oxide copolymers, cellulose, collagens, and chitins.